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Abstract Phoenix dactylifera L. and its wastes are known to be high in nutrients that are beneficial to human health. The study aimed to evaluate the antimicrobial, antibiofilm, and antiviral properties of Phoenix dactylifera L. pits extract (PDPE) in vitro. Gas chromatography-mass spectrometry (GC–MS) analysis indicated phenol, 2,5-bis(1,1-dimethyl ethyl), tetradecanoic acid, octaethylene glycol monododecyl ether, á-D-glucopyranosiduronic acid, and heptaethylene glycol monododecyl ether existence. The PDPE influenced pathogenic microorganisms, with inhibition zone diameters (IZDs) ranging from 10.0 to 35.0 mm. Staphylococcus aureus ATCC 5638 had the highest IZD, while Salmonella typhi DSM 17058 and Shigella sonnei DSM 5570 had the lowest. The antifungal effect observed only in spore failure or conidia formation. PDPE showed a 100% antibacterial spectrum against bacteria, with MIC values between 250 and 1000 µg/ml. MIC was only indicated with S. aureus of 500 µg/ml. MBC values ranged from 500 to 1000 g/ml, with MBC values of 500 g/ml for B. cereus, E. faecalis, S. typhi, and S. sonnei. The activity was 66.7% at 500 µg/ml, further concentrations of 125–250 g/ml had no antibacterial effect. PDPE biofilm inhibition % had the highest percentage of inhibition (98.59%) with S. aureus, B. cereus (94.12%), and E. coli (74.46%). With 50% (CC50) viral activity, the highest non-toxic PDPE dose was found to be at 123.0 µg/ml.

The citrus industry loses a significant amount of mandarin fruits either before or shortly after harvesting due to rind disorder. Different citrus cultivars are impacted by a physiological rind disorder that lowers fruit quality and marketability. Although the primary etiology of this condition is unknown, changes in relative humidity (RH) and rind water status can make it worse. The damage is initiated in the fall, especially following rain. It begins with irregular water-soaked areas that develop into dark-brown, necrotic lesions covering large portions of the fruit’s surface. The damage is evident in some citrus types such as Satsuma Owari mandarins and other cultivars. In this study, we attempted to understand and control the occurrence of this kind of rind disorder in Satsuma Owari mandarins growing under California conditions. Our data showed that fruit located in the outer part of the canopy suffer more than fruit in the interior canopy. We were able to reduce this damage in Satsuma Owari mandarins by applying 2,4-dichlorophenoxyacetic acid (2,4-D) at 16 milligrams/Liter (mg/L), gibberellic acid (GA3) at 20 mg/L, or Vapor Gard® at 0.5 percent (v/v) at the color break stage. However, GA3 caused a delay in color development by approximately four weeks. GA3-treated fruit changed their color completely four weeks after the control, and the rind damage was at a very low percentage. Delaying rind senescence could be a good strategy to reduce the damage in mandarin orchards. Data showed that in addition to the benefits of the different treatments on preventing rind disorder at harvest, they have some beneficial effects during storage for four weeks either at 0.5 or 7.5 °C.

Scarlet Royal, a mid-season ripening table grape, is one of the popular red grape varieties in California. However, its berries develop an undesirable astringent taste under certain conditions. Among the various factors contributing to the degradation of berry attributes, the levels and compositions of polyphenols play a fundamental role in defining berry quality and sensory characteristics. To comprehend the underlying mechanism of astringency development, Scarlet Royal berries with non-astringent attributes at the V7 vineyard were compared to astringent ones at the V9 vineyard. Biochemical analysis revealed that the divergence in berry astringency stemmed from alterations in its polyphenol composition, particularly tannins, during the late ripening stage at the V9 vineyard. Furthermore, transcriptomic profiling of berries positively associated nineteen flavonoid/proanthocyanidins (PAs) structural genes with the accumulation of PAs in V9 berries. The identification of these genes holds significance for table grape genetic improvement programs. At a practical level, the correlation between the taste panel and tannin content revealed a threshold level of tannins causing an astringent taste at approximately 400 mg/L. Additionally, berry astringency at the V9 vineyard was linked to a lower number of clusters and yield during the two study seasons, 2016 and 2017. Furthermore, petiole nutrient analysis at bloom showed differences in nutrient levels between the two vineyards, including higher levels of nitrogen and potassium in V9 vines compared to V7. It’s worth noting that V9 berries at harvest displayed a lower level of total soluble solids and higher titratable acidity compared to V7 berries. In conclusion, our results indicate that the accumulation of tannins in berries during the ripening process results in a reduction in their red color intensity but significantly increases the astringency taste, thereby degrading the berry quality attributes. This study also highlights the association of high nitrogen nutrient levels and a lower crop load with berry astringency in table grapes, paving the way for further research in this area

Citrus fruit’s appearance is the primary criterion used to assess its quality for the fresh market, hence the rind’s condition is a crucial quality trait. Pre-harvest rind disorder is one of the major physiological problems in mandarins. The disorder occurs right before harvest following rain events in some Mandarin varieties. Despite the economic damage caused by this kind of disorder, very limited information is available about the molecular mechanisms underlying the occurrence of this disorder. In the present study, we evaluated the primary metabolites, antioxidants, and hormones associated with the pre-harvest rind disorder in Mandarins. The study was carried out using ten-year-old ‘Owari’ Satsuma mandarin trees grafted on ‘Carrizo’ rootstock and grown in a commercial orchard in San Joaquin Valley, California, USA. Samples were collected from healthy tissue of healthy fruit (HF_HT), healthy tissue of damaged fruit (DF_HT), and damaged tissue of damaged fruit (DF_DT). Damaged fruit (DF_HT and DF_DT) showed lower cellulose concentrations than healthy fruit tissues (HF_HT), however, had similar contents of pectin and hemicellulose. The antioxidant activities showed no significant difference in all paired comparisons between samples as expressed in the malondialdehyde (MDA) content. However, DF_DT had a higher H2O2 content compared to HF_HT, but DF_HT had a similar content to that of HF_HT. Furthermore, peroxidase (POD) and polyphenol oxidase (PPO) activities were increased in DF_DT compared to HF_HT (P = 0.0294) and DF_HT (P = 0.0044), respectively. Targeted metabolomics analysis revealed that a total of 76 metabolites were identified in Satsuma rind tissues, and the relative concentrations of 43 metabolites were significantly different across studied samples. The hormonal analysis showed the involvement of jasmonate O-methyltransferase, jasmonic acid-amido synthetase JAR1-like, and JA-isoleucine may key role in causing the rind disorder in mandarins. In addition, the damaged fruit tissues have a higher level of jasmonic acid (JA), 12-oxo-phytodienoic acid, and JA-isoleucine than undamaged tissue.

Red color resulted from anthocyanin pigment, is an essential trait for premium table grape production. Anthocyanin biosynthesis occurs through the flavonoid pathway which includes several enzymatic reactions coded by different genes. The expression of these genes is regulated by different cultural practices, cultivars, environmental conditions, and plant hormones. Recently, we reported that the anthocyanin pathway is regulated by several factors such as light and antioxidant activity. Despite the advances in cultural practices, it is still challenging to produce table grapes with high coloration, especially under the current and expected global climate change in warmer areas such as California. In the current study, we deployed two approaches to improve the accumulation of red pigment in table grapes. The first approach involves improving the expression of critical genes involved in the anthocyanin pathway through hormonal treatments and light manipulation using a reflective ground cover (RGC). The second approach was to reduce the negative effect of heat stress through stimulation of the antioxidant pathway to help remove free radicals. Treatments included ethephon (ET) at 600 mg/L, silicon (Si) at 175 mg/L, and a commercial light-reflective white ground cover (RGC) alone and in various combinations. Treatments were conducted either with or without a combination of cluster-zone leaf removal at veraison (LR) on Flame seedless (Vitis vinifera L.). Data collected in 2019 and 2020 showed that the best treatment to improve berry coloration was using ET in combination with Si and RGC, applied at veraison. Adding the LR to this combination did not improve berry color any further, but rather caused a reduction in color development. RGC without conducting LR at veraison significantly increased the quantity of reflected blue and red lights as well as the red (R) to far-red (FR) ratio (R: FR) around clusters. Results were in accordance with the increase in gene expression of flavonoid-3-O-glucosyltransferase (UFGT), a key gene in the anthocyanin biosynthesis pathway, as well as Peroxidase dismutase (POD). Manipulating the light spectrum and application of silicon in combination with the ethephon treatment could be used in table grape vineyards to improve the ethylene-induced anthocyanin accumulation and coloration.

The defect in the hepatobiliary transport system results in an impairment of bile flow, leading to accumulation of toxic compounds with subsequent liver disorders. Vincamine, a plant indole alkaloid that is utilized as a dietary supplement, has been known for its promising pharmacological activities. For the first time, the present study was planned to estimate, at the molecular level, the potentiality of vincamine against alfa-naphthyl isothiocyanate (ANIT)-induced hepatic cholestasis. Liver function tests were analyzed. Hepatic activity of SOD and levels of GSH and MDA were assessed. Hepatic contents of bax, bcl2, NF-kB, PPARγ, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of NF-kB, IL-1β, IL-6, TNFα, PDGF, klf6, PPARγ, and P53 were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin & eosin staining. ANIT-induced hepatic cholestasis elevated liver function tests, including AST, ALT, GGT, ALP, and total bilirubin. ANIT reduced the protein expression of NTCP and BSEP hepatic transporters. It induced the expression of the inflammatory genes, TNFα, IL-6, IL-1β, and PDGF, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and PPARγ. Also, antioxidant markers were reduced during ANIT induction such as GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway, while MDA levels were elevated. Furthermore, the expression of P53 gene, bax and cleaved caspase 3 proteins were activated, while bcl2 was inhibited. Also, the histopathological analysis showed degeneration of hepatocytes and inflammatory cellular infiltrates. However, vincamine treatment modulated all these markers. It improved liver function tests. It inhibited the expression of NF-kB, TNFα, IL-6, IL-1β and PDGF and activated the expression of klf6 and PPARγ. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway. Additionally, it inhibited expression of P53 gene, bax and cleaved caspase 3 proteins. More interestingly, vincamine showed better outcomes on the hepatic histopathological analysis and improved the alterations induced by ANIT. Vincamine alleviated hepatic dysfunction during ANIT-induced intrahepatic cholestasis through its anti-inflammatory and antioxidant efficacies by the modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways., (© 2024. The Author(s).)

Sepsis is a pathological and biochemical disorder induced by numerous infections, leading to critical illness and a high mortality rate worldwide. Vincamine is an indole alkaloid compound obtained from the leaves of Vinca minor. The present study aims to investigate the hepato-protective activity of vincamine during colon ligation puncture (CLP)-induced sepsis at the molecular level. Sepsis was induced using the CLP model. Liver function enzymes such as ALT and AST were analyzed. The hepatic antioxidant status (SOD and GSH), lipid peroxidation (MDA), the pro-inflammatory cytokines (TNFα, IL-6, and IL-1β), bax, bcl2, and cleaved caspase 3 proteins were estimated. Nrf-2 and Keap-1 protein expression was evaluated using western blotting. Histopathological investigation of liver tissues was also performed. CLP-induced sepsis led to liver injury through the elevation of ALT and AST liver enzymes. Oxidative stress was initiated during CLP via the suppression of hepatic GSH content and SOD activity and the elevation of MDA. The inflammatory condition was activated by the upregulation of TNFα, IL-6, IL-1β, and Keap-1 and the downregulation of Nrf-2 proteins. The apoptosis was initiated through the activation of bax and cleaved caspase 3 protein expression and inhibition of bcl2 protein expression. However, vincamine significantly improved the hepatic histological abnormalities and decreased liver enzymes (ALT and AST). It ameliorated oxidative stress, as evidenced by reducing the hepatic MDA content and increasing the SOD activity and GSH content. Moreover, vincamine reduced the hepatic content of TNFα, IL-6, IL-1β, and Keap-1 and increased Nrf-2 protein expression. Additionally, it upregulated bcl2 protein expression and downregulated bax and cleaved caspase 3 protein expression. Vincamine exhibited hepato-protective potential during CLP-induced sepsis via the cross-connection of antioxidant, anti-inflammatory, and anti-apoptotic activities by modulating TNFα/IL-6/IL-1β/Nrf-2/Keap-1 and regulating bax/bcl2/cleaved caspase 3 signaling pathways., (© 2024. The Author(s).)

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

Purpose: Globally, sepsis, which is a major health issue resulting from severe infection-induced inflammation, is the fifth biggest cause of death. This research aimed to evaluate, for the first time, the molecular effects of gabapentin's possible nephroprotective potential on septic rats by cecal ligation and puncture (CLP)., Methods: Sepsis was produced by CLP in male Wistar rats. Evaluations of histopathology and renal function were conducted. MDA, SOD, GSH, TNF-α, IL-1β, and IL-6 levels were measured. qRT-PCR was utilized to determine the expression of Bax, Bcl-2, and NF-kB genes. The expression of Nrf-2 and HO-1 proteins was examined by western blotting., Results: CLP caused acute renal damage, elevated the blood levels of creatinine, BUN, TNF-α, IL-1β, and IL-6, reduced the expression of Nrf-2 and HO-1 proteins and the Bcl-2 gene expression, and upregulated NF-kB and Bax genes. Nevertheless, gabapentin dramatically diminished the degree of the biochemical, molecular, and histopathological alterations generated by CLP. Gabapentin reduced the levels of proinflammatory mediators and MDA, improved renal content of GSH and SOD, raised the expression of Nrf-2 and HO-1 proteins and Bcl-2 gene, and reduced the renal expression of NF-kB and Bax genes., Conclusion: Gabapentin mitigated the CLP-induced sepsis-related acute kidney injury through up-regulating Nrf-2/HO-1 pathway, repressing apoptosis, and attenuating the oxidative stress status by reducing the levels of the proinflammatory mediators and enhancing the antioxidant status., (© 2023. The Author(s).)

Aim: Sepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats., Main Methods: CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined., Key Findings: CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone., Significance: LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease that leads to respiratory failure and death. Vincamine is an indole alkaloid obtained from the leaves of Vinca minor and acts as a vasodilator. The present study aims to investigate the protective activity of vincamine against EMT in bleomycin (BLM)-induced pulmonary fibrosis via assessing the apoptotic and TGF-β1/p38 MAPK/ERK1/2 signaling pathways. In bronchoalveolar lavage fluid, protein content, total cell count, and LDH activity were evaluated. N-cadherin, fibronectin, collagen, SOD, GPX, and MDA levels were determined in lung tissue using ELISA. Bax , p53 , bcl2 , TWIST , Snai1 , and Slug mRNA levels were examined using qRT-PCR. Western blotting was used to assess the expression of TGF-β1, p38 MAPK, ERK1/2, and cleaved caspase 3 proteins. H & E and Masson's trichrome staining were used to analyze histopathology. In BLM-induced pulmonary fibrosis, vincamine reduced LDH activity, total protein content, and total and differential cell count. SOD and GPX were also increased following vincamine treatment, while MDA levels were decreased. Additionally, vincamine suppressed the expression of p53 , Bax , TWIST , Snail , and Slug genes as well as the expression of factors such as TGF-β1, p/t p38 MAPK, p/t ERK1/2, and cleaved caspase 3 proteins, and, at the same time, vincamine increased bcl2 gene expression. Moreover, vincamine restored fibronectin, N-Catherine, and collagen protein elevation due to BLM-induced lung fibrosis. In addition, the histopathological examination of lung tissues revealed that vincamine attenuated the fibrotic and inflammatory conditions. In conclusion, vincamine suppressed bleomycin-induced EMT by attenuating TGF-β1/p38 MAPK/ERK1/2/TWIST/Snai1/Slug/fibronectin/N-cadherin pathway. Moreover, it exerted anti-apoptotic activity in bleomycin-induced pulmonary fibrosis.

Tamarindus indica Linn (tamarind, F. Leguminosae) is one of the most widely consumed edible fruits in the world. Phytochemical investigation of tamarind pulp n -butanol fraction yielded one new (+)-pinitol glycoside compound 1 (25% w / w ), and 1D, 2D NMR, and HRESIMS investigation were used to confirm the new compound's structure. (+)-Pinitol glycoside showed anti-Alzheimer potential that was confirmed in prophylactic and treatment groups by decreasing time for the T-maze test; decreased TAO, brain and serum AChE, MDA, tau protein levels, and β amyloid peptide protein levels; and increasing GPX, SOD levels, and in vivo regression of the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. The reported molecular targets for human Alzheimer's disease were then used in a network pharmacology investigation to examine their complex interactions and identify the key targets in the disease pathogenesis. An in silico-based analysis (molecular docking, binding free energy calculation (Δ G Binding ), and molecular dynamics simulation) was performed to identify the potential targets for compound 1 . The findings of this study may lead to the development of dietary supplements for the treatment of Alzheimer's disease.

Aims: Sepsis is a severe inflammatory response to infection with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths yearly. Furthermore, sepsis remains the fifth most common cause of death worldwide. The present study aimed to examine, for the first time, the potential hepatoprotective activity of gabapentin on cecal ligation and puncture (CLP)-induced sepsis in rats at the molecular level., Main Methods: CLP was used as a model of sepsis in male Wistar rats. Histological examination and liver functions were evaluated. Levels of MDA, GSH, SOD, IL-6, IL-1β, and TNF-α were investigated using ELISA. mRNA levels of Bax, Bcl-2, and NF-kB were assessed by qRT-PCR. Western blotting investigated the expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins., Key Findings: CLP resulted in liver damage, elevated serum levels of ALT, AST, ALP, MDA, TNF-α, IL-6, and IL-1β, increased expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins, and upregulated Bax and NF-κB genes expression while it down-regulated Bcl-2 gene expression. However, gabapentin treatment significantly reduced the severity of CLP-induced biochemical, molecular, and histopathological changes. Gabapentin attenuated the levels of the proinflammatory mediators, decreased the expression of JNK1/2, ERK1/2, and cleaved caspase 3 proteins, suppressed Bax and NF-κB genes expression and increased the expression of the Bcl-2 gene., Significance: Consequently, Gabapentin reduced hepatic injury resulting from CLP-induced sepsis by reducing proinflammatory mediators, attenuating apoptosis, and inhibiting the intracellular MAPK (ERK1/2, JNK1/2)-NF-kB signaling pathway., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Renal ischemia/reperfusion (IR) injury is characterized by an unexpected impairment of blood flow to the kidney. Azilsartan is an angiotensin receptor blocker that is approved for the management of hypertension. The present study aimed to investigate, on molecular basics, the nephroprotective activity of azilsartan on renal IR injury in rats. Rats were assigned into four groups: (1) Sham group, (2) Azilsartan group, (3) IR group, and (4) IR/Azilsartan-treated group. Histological examination and renal function were evaluated. Levels of KIM-1, HMGB1, caspase 3, GPX, SOD, NF-κB, and p53 proteins were investigated using ELISA. mRNA levels of IL-1β , IL6 , IL10 , TNF-α , NF-κB , p53 , and bax were assessed by qRT-PCR. Expression of p38, JNK, and ERK1/2 proteins was investigated by Western blotting. IR injury resulted in tissue damage, elevation of creatinine, BUN, KIM-1, HMGB1, caspase 3, NF-κB, and p53 levels, decreasing GPX and SOD activities, and up-regulation of NF-κB , IL-1β , IL6 , TNF-α , p53 , and bax genes. Furthermore, it up-regulated the expression of phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Interestingly, treatment of the injured rats with azilsartan significantly alleviated IR injury-induced histopathological and biochemical changes. It reduced the creatinine, BUN, KIM-1, HMGB1, caspase-3, NF-κB, and p53 levels, elevated GPX and SOD activities, down-regulated the expression of NF-κB , IL-1β , IL6 , TNF-α , p53 , and bax genes, and up-regulated IL10 gene expression. Furthermore, it decreased the phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Azilsartan exhibited nephroprotective activity in IR-injured rats via its antioxidant effect, suppression of inflammation, attenuation of apoptosis, and inhibition of HMGB1/NF-κB/p38/ERK1/2/JNK signaling pathway.

LC-HRESIMS metabolomic profiling of Olea europaea L. cv. Picual (OEP) (Saudi Arabian olive cultivar, F. Oleacea) revealed 18 compounds. Using pharmacology networking to specify the targets of the identified compounds with a relationship to Alzheimer's disease, it was possible to identify the VEGFA, AChE, and DRD2 genes as the top correlated genes to Alzheimer's disease with 8, 8, and 6 interactions in the same order. The mechanism of action on cellular components, biological processes, and molecular functions was determined by gene enrichment analysis. A biological pathway comparison revealed 13 shared pathways between the identified genes and Alzheimer protein genes (beta-amyloid band tau proteins). The suggested extract's anti-Alzheimer potential in silico screening was confirmed through in vivo investigation in regressing the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model (protective and therapeutic effects, 100 mg/kg b.w.). In vivo results suggested that OEP extract significantly improved Alzheimer's rats, which was indicated by the crude extract's ability to improve T-maze performance; lower elevated serum levels of AChE, AB peptide, and Ph/T ratio; and normalize the reduced level of TAC during the study. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.

Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine its anticancer activity against HepG2 and A549 cancer cells, and investigate the possible molecular mechanism underlying this activity by examining its ability to inhibit the topo I/II activity and to induce the apoptotic and necro-apoptotic pathways. Molecular docking, cell viability, cell migration, colony formation, cell cycle, Annexin V, lactate dehydrogenase (LDH) release, ELISA, and western blotting assays were utilized. Molecular docking results showed that this novel ciprofloxacin derivative exerted dual topo I and topo II binding and inhibition. It significantly inhibited the proliferation of A549 and HepG2 cancer cells and decreased their cell migration and colony formation abilities. In addition, it significantly increased the % of apoptotic cells, caused cell cycle arrest at G2/M phase, and elevated the LDH release levels in both cancer cells. Furthermore, it increased the expression of cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins. This novel ciprofloxacin derivative exerted substantial dual inhibition of topo I/II enzyme activities, showed antiproliferative activity, suppressed the cell migration and colony formation abilities for A549 and HepG2 cancer cells and activated the apoptotic pathway. In addition, it initiated another backup deadly pathway, necro-apoptosis, through the activation of the RIPK1/RIPK3/MLKL pathway.

Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2 , and increased the mRNA level of bax . Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways.

Ischemia is a deadly disease featured by restricted perfusion to different organs in the body. An increase in the accumulation of reactive oxygen species and cell debris is the driving force for inducing many oxidative, inflammatory and apoptotic signaling pathways. However, the number of therapeutics existing for ischemic stroke patients is limited and there is insufficient data on their efficiency, which warrants the search for novel therapeutic candidates from natural sources. Herein, a comprehensive survey was done on the reported functional food bioactives ( ca. 152 compounds) to manage or protect against health consequences of myocardial and cerebral ischemia. Furthermore, we reviewed the reported mechanistic studies for their anti-ischemic potential. Subsequently, network pharmacology- and in silico -based studies were conducted using the reported myocardial and cerebral ischemia-relevant molecular targets to study their complex interactions and highlight key targets in disease pathogenesis. Subsequently, the most prominent 20 compounds in the literature were used in a comprehensive in silico -based analysis (inverse docking, Δ G calculation and molecular dynamics simulation) to determine other potential targets for these compounds and their probable interactions with different signaling pathways relevant to this disease. Many functional food bioactives, belonging to different chemical classes, i.e. , flavonoids, saponins, phenolics, alkaloids, iridoids and carotenoids, were proven to exhibit multifactorial effects in targeting the complex pathophysiology of ischemic conditions. These merits make them valuable therapeutic agents that can outperform the conventional drugs, and hence they can be utilized as add-ons to the conventional therapy for the management of different ischemic conditions; however, their rigorous clinical assessment is necessary.

Inflammation is a critical defensive mechanism mainly arising due to the production of prostaglandins via cyclooxygenase enzymes. This study aimed to examine the anti-inflammatory activity of fatty acid glucoside (FAG), which is isolated from Ficus benghalensis against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The cytotoxic activity of the FAG on RAW 264.7 macrophages was evaluated with an MTT assay. The levels of PGE2 and NO and the activity of iNOS, COX-1, and COX-2 enzymes in LPS-stimulated RAW 264.7 cells were evaluated. The gene expression of IL-6, TNF-α, and PGE2 was investigated by qRT-PCR. The expression of epidermal growth factor receptor (EGFR), Akt, and PI3K proteins was examined using Western blotting analysis. Furthermore, molecular docking of the new FAG against EGFR was investigated. A non-cytotoxic concentration of FAG increased NO release and iNOS activity, inhibited COX-1 and COX-2 activities, and reduced PGE2 levels in LPS-stimulated RAW 264.7 cells. It diminished the expression of TNF-α, IL-6, PGE2, EGFR, Akt, and PI3K. Furthermore, the molecular docking study proposed the potential direct binding of FAG with EGFR with a high affinity. This study showed that FAG is a natural EGFR inhibitor, NO-releasing, and COX-inhibiting anti-inflammatory agent via EGFR/Akt/PI3K pathway inhibition.

The present work deals with the development of metformin-loaded ethosomes for localized treatment of melanoma and wound healing. Different ethosomal formulations were prepared using different concentrations of ethanol adopting injection technique. The developed formulations were investigated for entrapment efficiency, ex-vivo skin permeation, vesicle size, morphology and permeation kinetics. The optimized formulation was loaded in 5 % carbomer gel that was evaluated for skin permeation, cytotoxic effect against melanoma mice B16 cell line and for wound healing action. Ethosomes having 30 % v/v ethanol displayed superior entrapment for metformin % (55.3 ± 0.07); and a highly efficient permeation via mice skin (85.8 ± 3.7). The related carbomer ethosomal gel exhibited higher skin permeation compared to the untreated metformin gel (P < 0.001). The metformin ethosomes had a substantial antiproliferative activity against melanoma B16 cells compared to corresponding metformin solution as shown by the lower IC50 values (56.45 ± 1.47 and 887.3 ± 23.2, respectively, P < 0.05) and tumour cell viability (P < 0.05). The ethosomal system had a significant wound healing action in mice (80.5 ± 1.9%) that was superior to that of the marketed product Mebo® ointment (56 ± 1 %), P < 0.05. This ethosomal system demonstrated outstanding induction of the mRNA levels of growth factors (IGF-1, FGF-1, PDGF-B and TGF-β) that are essential in the healing process. Those findings were supported by histopathologic examination of wound sections of different treated groups. Thus, the study proved that metformin ethosomes as a promising drug delivery system and a conceivable therapeutic approach for treatment of melanoma and wound healing., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background/aim: SARS-CoV-2 is one of the coronavirus families that emerged at the end of 2019. It infected the respiratory system and caused a pandemic worldwide. Fluoroquinolones (FQs) have been safely used as antibacterial agents for decades. The antiviral activity of FQs was observed. Moreover, substitution on the C-7 position of ciprofloxacin enhanced its antiviral activity. Therefore, this study aims to investigate the antiviral activity of 7-(4-(N-substituted-carbamoyl-methyl)piperazin-1yl)-chalcone in comparison with ciprofloxacin against SARS-CoV-2 main protease (M pro )., Materials and Methods: Vero cells were infected with SARS-CoV-2. After treatment with ciprofloxacin and the chalcone at the concentrations of 1.6, 16, 160 nmol/L for 48 h, SARS-CoV-2 viral load was detected using real-time qPCR, SARS-CoV-2 infectivity was determined using plaque assay, and the main protease enzyme activity was detected using in vitro 3CL-protease inhibition assay. The activity of the chalcone was justified through molecular docking within SARS-CoV-2 M pro , in comparison with ciprofloxacin., Results: The new chalcone significantly inhibited viral load replication where the EC50 was 3.93 nmol/L, the plaque formation ability of the virus was inhibited to 86.8% ± 2.47. The chalcone exhibited a significant inhibitory effect against SARS-CoV-2 M pro in vitro in a dose-dependent manner. The docking study into SARS-CoV-2 M pro active site justified the importance of adding a substitution to the parent drug. Additionally, the assessment of the drug-likeness properties indicated that the chalcone might have acceptable ADMET properties., Conclusion: The new chalcone might be useful and has new insights for the inhibition of SARS-CoV-2 M pro ., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Keratitis is a global health issue that claims the eye sight of millions of people every year. Dry eye, contact lens wearing and refractive surgeries are among the most common causes. The resistance rate among fluoroquinolone antibiotics is >30%. This study aims at formulating a newly synthesized ciprofloxacin derivative (2b) niosomes and Solulan C24-, sodium cholate- and deoxycholate-modified niosomes. The prepared niosomal dispersions were characterized macroscopically and microscopically (SEM) and by percentage entrapment efficiency, in vitro release and drug release kinetics. While the inclusion of Solulan C24 produced something discoidal-shaped with a larger diameter, both cholate and deoxycholate were unsuccessful in forming niosomes dispersions. Conventional niosomes and discomes (Solulan C24-modified niosomes) were selected for further investigation. A corneal ulcer model inoculated with colonies of Pseudomonas aeruginosa in rabbits was developed to evaluate the effectiveness of keratitis treatment of the 2b-loaded niosomes and 2b-loaded discomes compared with Ciprocin ® (ciprofloxacin) eye drops and control 2b suspension. The histological documentation and assessment of gene expression of the inflammatory markers (IL-6, IL1B, TNFα and NF-κB) indicated that both 2b niosomes and discomes were superior treatments and can be formulated at physiological pH 7.4 compatible with the ocular surface, compared to both 2b suspension and Ciprocin ® eye drops.

Insulin resistance contributes to several disorders including type 2 diabetes and cardiovascular diseases. Carpachromene is a natural active compound that inhibits α-glucosidase enzyme. The aim of the present study is to investigate the potential activity of carpachromene on glucose consumption, metabolism and insulin signalling in a HepG2 cells insulin resistant model. A HepG2 insulin resistant cell model (HepG2/IRM) was established. Cell viability assay of HepG2/IRM cells was performed after carpachromene/metformin treatment. Glucose concentration and glycogen content were determined. Western blot analysis of insulin receptor, IRS1, IRS2, PI3k, Akt, GSK3, FoxO1 proteins after carpachromene treatment was performed. Phosphoenolpyruvate carboxykinase (PEPCK) and hexokinase (HK) enzymes activity was also estimated. Viability of HepG2/IRM cells was over 90% after carpachromene treatment at concentrations 6.3, 10, and 20 µg/mL. Treatment of HepG2/IRM cells with carpachromene decreased glucose concentration in a concentration- and time-dependant manner. In addition, carpachromene increased glycogen content of HepG2/IRM cells. Moreover, carpachromene treatment of HepG2/IRM cells significantly increased the expression of phosphorylated/total ratios of IR, IRS1, PI3K, Akt, GSK3, and FoxO1 proteins. Furthermore, PEPCK enzyme activity was significantly decreased, and HK enzyme activity was significantly increased after carpachromene treatment. The present study examined, for the first time, the potential antidiabetic activity of carpachromene on a biochemical and molecular basis. It increased the expression ratio of insulin receptor and IRS1 which further phosphorylated/activated PI3K/Akt pathway and phosphorylated/inhibited GSK3 and FoxO1 proteins. Our findings revealed that carpachromene showed central molecular regulation of glucose metabolism and insulin signalling via IR/IRS1/ PI3K/Akt/GSK3/FoxO1 pathway.

Herein, we investigated both fruits and leaves of Morus macroura Miq. as a potential source of bioactive compounds against Alzheimer's disease (AD). LC-HRMS-assisted chemical profiling of its extracts showed that they are a rich source of diverse phytochemicals. Among the 29 identified compounds in both the fruit and leaf extracts, moracin D, chrysin, resveratrol, and ferulic acid were predicted to pass the human blood-brain barrier (BBB), and hence, reach their therapeutic targets in the brain. Subsequently, these compounds were subjected to a comprehensive pharmacophore-based screening for their protein targets relevant to AD using two independent software programs (i.e. Swiss Target Prediction and PharmMapper). The results of this initial virtual screening were further refined by a number of docking and molecular dynamic simulation experiments to suggest a number of crucial AD-related proteins (e.g. acetylcholine esterase, β-secretase, and monoamine oxidase) as potential targets for these compounds. Finally, in vitro testing was performed to validate the in silico investigation's results, where chrysin, resveratrol, and ferulic acid were found to inhibit the predicted AD-related enzymes with IC 50 values comparable with those of the reference inhibitors. Additionally, they were able to inhibit the aggregation of amyloid-beta, one of the hallmarks in AD pathogenesis, and to exhibit considerable antioxidant capacity. Our results highlighted Morus macroura compounds as future anti-Alzheimer chemical leads.

Background/aim: This study aimed to investigate the effect of the new ciprofloxacin chalcone [7-(4-(N-substituted carbamoyl methyl) piperazin-1 yl)] on the proliferation, migration, and metastasis of MCF-7 and MDA-MB-231 breast cancer cell lines., Materials and Methods: Cell viability, colony formation and cell migration abilities were analysed. Cell cycle distribution and apoptosis were examined by flow cytometry. The molecular mechanism underlying chalcone's activity was investigated using qRT-PCR and western blotting., Results: This new ciprofloxacin chalcone significantly inhibited proliferation, colony formation, and cell migration abilities of both cancer cell lines. Furthermore, it initiated apoptosis and caused cell cycle arrest at G2/M and S phase in MCF-7 and MDA-MB-231 cell lines, respectively. In addition, it up-regulated the expression of pro-apoptotic factors, p53, PUMA and NOXA, and down-regulated the expression of anti-apoptotic factors, MDM2 and MDM4. At the same time, it inhibited epithelial-mesenchymal transition by increasing the expression of E-cadherin and decreasing the expression of TGF-β1, SNAI1, TWIST1, MMP2, and MMP9., Conclusion: This new ciprofloxacin chalcone exhibited promising apoptotic and anti-metastatic activities against MCF-7 and MDA-MB-231 breast cancer cell lines, and, therefore, is an attractive molecule for drug development in the treatment of breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Ciprofloxacin has been used as an antibiotic in the clinic for decades. Recently, ciprofloxacin and its derivatives have shown promising anti-proliferative and cytotoxic activities against several malignant cells. The aim of this study was to investigate the effect of a new derivative of ciprofloxacin on colorectal cancer (HCT116) and non-small lung carcinoma (A549) cells., Materials and Methods: Cell viability was detected by the MTT assay. Flow cytometry was used to examine the cell cycle and apoptosis. Expression of bax, bcl2, p53 and p21 was investigated by qRT-PCR and western blotting., Results: Ciprofloxacin-derivative had an anti-proliferative effect on both cell lines in a concentration-dependent manner and caused cell cycle arrest at the G 2 /M phase and apoptosis. p53 and Bax proteins were overexpressed, while p21 and bcl2 gene expression was decreased after treatment with the ciprofloxacin derivative., Conclusion: This new ciprofloxacin derivative can be potentially used for the treatment of colorectal cancer and non-small lung carcinoma., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)